Spiro-piperidine derivatives

ABSTRACT

The present invention is concerned with novel spiro-piperidine derivatives as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The active compounds of the present invention are useful in the prevention and/or treatment of anxiety and depressive disorders and other diseases. 
     In particular, the present invention is concerned with compounds of the general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1  to R 5 , R 5 ′, X, Y and A are as defined in the specification.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06127078.1, filed Dec. 22, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Vasopressin is a 9 amino acid peptide mainly produced by theparaventricular nucleus of the hypothalamus. Three vasopressinreceptors, all belonging to the class I G-protein coupled receptors, areknown. The V1a receptor is expressed in the brain, liver, vascularsmooth muscle, lung, uterus and testis, the V1b or V3 receptor isexpressed in the brain and pituitary gland, the V2 receptor is expressedin the kidney where it regulates water excretion and mediates theantidiuretic effects of vasopressin.

In the periphery vasopressin acts as a neurohormone and stimulatesvasoconstriction, glycogenolysis and antidiuresis. In the brainvasopressin acts as a neuromodulator and is elevated in the amygdaladuring stress (Ebner, K., C. T. Wotjak, et al. (2002). “Forced swimmingtriggers vasopressin release within the amygdala to modulatestress-coping strategies in rats.” Eur J Neurosci 15(2): 384-8). The V1areceptor is extensively expressed in the brain and particularly inlimbic areas like the amygdala, lateral septum and hippocampus which areplaying an important role in the regulation of anxiety. Indeed V1aknock-out mouse show a reduction in anxious behavior in the plus-maze,open field and light-dark box (Bielsky, I. F., S. B. Hu, et al. (2003).“Profound Impairment in Social Recognition and Reduction in Anxiety-LikeBehavior in Vasopressin V1a Receptor Knockout Mice.”Neuropsychopharmacology). The downregulation of the V1a receptor usingantisense oligonucleotide injection in the septum also causes areduction in anxious behavior (Landgraf, R., R. Gerstberger, et al.(1995). “V1 vasopressin receptor antisense oligodeoxynucleotide intoseptum reduces vasopressin binding, social discrimination abilities, andanxiety-related behavior in rats.” Regul Pept 59(2): 229-39).

The V1a receptor is also mediating the cardiovascular effects ofvasopressin in the brain by centrally regulating blood pressure andheart rate in the solitary tract nucleus (Michelini, L. C. and M. Morris(1999). “Endogenous vasopressin modulates the cardiovascular responsesto exercise.” Ann N Y Acad Sci 897: 198-211). In the periphery itinduces the contraction of vascular smooth muscles and chronicinhibition of the V1a receptor improves hemodynamic parameters inmyocardial infarcted rats (Van Kerckhoven, R., I. Lankhuizen, et al.(2002). “Chronic vasopressin V(1A) but not V(2) receptor antagonismprevents heart failure in chronically infarcted rats.” Eur J Pharmacol449(1-2): 135-41).

SUMMARY OF THE INVENTION

The present invention provides novel spiro-piperidine derivatives as V1areceptor antagonists, their manufacture, pharmaceutical compositionscontaining them and their use for the treatment of anxiety anddepressive disorders and other diseases.

In particular, the present invention provides compounds of formula (I)

wherein

-   -   X is O and Y is CH₂,    -   X is O and Y is C═O,    -   X is C═O and Y is NR⁶,    -   X—Y is CH═CH,    -   X—Y is CH₂—CH₂,    -   X is C═O and Y is O,    -   X is CH₂ and Y is NR⁶, or    -   X is CH₂ and Y is O;        A is selected from the group consisting of

-   R¹, R², R³ and R⁴ are each independently    -   hydrogen,    -   halo,    -   C₁₋₆-alkyl, optionally substituted by OH    -   halo-C₁₋₆-alkyl,    -   C₁₋₆-alkoxy, optionally substituted by OH, or    -   halo-C₁₋₆-alkoxy;-   R⁵ and R^(5′) are each independently hydrogen or methyl;-   R⁶ is hydrogen or C₁₋₆-alkyl;-   R⁷ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH, or    -   —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b);-   R⁸ is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano, or    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;-   R⁹ is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   R¹⁰ is hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy,    halo-C₁₋₆-alkoxy, or —O—C₂₋₁₀-alkenyl;-   R¹¹ is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   or R¹⁰ and R¹¹ are bound together to form a ring with the benzo    moiety, wherein —R¹⁰-R¹¹— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R¹² is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j)    -   —O-benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   —(C₁₋₃-alkylene)-R^(m),        -   wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4-            to 6-membered heterocycloalkyl or 3 to 6-membered            cycloalkyl,            -   each optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano, or    -   —NR^(n)R^(o);-   or R¹¹ and R¹² are bound together to form a ring with the benzo    moiety, wherein    -   —R¹¹-R¹²— is —O—(CH₂)_(n)—C(O)—,        -   —C(O)—(CH₂)_(n)—O—, or        -   —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R^(a), R^(b), R^(i) and R^(j) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-NR^(k)R^(l),        -   wherein R^(k) and R^(l) are each independently hydrogen or            C₁₋₆-alkyl,    -   or R^(a) and R^(b), or R^(i) and R^(j) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;-   R^(c), R^(d), R^(g), R^(h), R^(n) and R^(o) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —C(O)R^(e), or —S(O)₂R^(e)        -   wherein R^(e) is selected from the group of            -   hydrogen,            -   C₁₋₆-alkyl, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano;        -   or R^(c) and R^(d), or R^(n) and R^(o) together with the            nitrogen to which they are bound form a five or six membered            heterocycle comprising one or two heteroatoms selected from            the group of nitrogen, oxygen and sulfur;            R^(f) is selected from the group of    -   hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy; and    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;        or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to a person skilled in the art. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below, by methods described in references cited in thetext or in the examples, or by methods known in the art.

The compounds of formula (I) possess pharmaceutical activity, inparticular they are modulators of V1a receptor activity. Moreparticular, the compounds are antagonists of the V1a receptor. Thepresent invention provides methods for the treatment of dysmenorrhea,hypertension, chronic heart failure, inappropriate secretion ofvasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsivedisorder, anxiety and depressive disorders. The preferred indicationswith regard to the present invention are the treatment of anxiety anddepressive disorders.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

In the present description, the term “alkyl,” alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated hydrocarbon radical. The term “C₁₋₆-alkyl” denotes a saturatedstraight- or branched-chain hydrocarbon group containing from 1 to 6carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, the isomeric pentyls and the like. A preferredsub-group of C₁₋₆-alkyl is C₁₋₄-alkyl, i.e. with 1-4 carbon atoms.

In the present invention, the term “alkylene” refers to a linear orbranched saturated divalent hydrocarbon radical. In particular,“C₁₋₆-alkylene” means a linear saturated divalent hydrocarbon radical ofone to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g. methylene, ethylene,2,2-dimethylethylene, n-propylene, 2-methylpropylene, and the like.

In the present description, the terms “alkoxy” and “C₁₋₆-alkoxy” referto the group R′—O—, wherein R′ is alkyl or C₁₋₆-alkyl as defined above.Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, tert-butoxy, sec-butoxy and the like. A preferred sub-group ofC₁₋₆-alkoxy, and still more preferred alkoxy groups are methoxy and/orethoxy.

In the present description, the terms “thioalkyl” and “C₁₋₆-thioalkyl”refer to the group R′—S—, wherein R′ is alkyl or C₁₋₆-alkyl as definedabove.

The terms “C₁₋₆-hydroxyalkyl” and “C₁₋₆-alkyl substituted by OH” denotea C₁₋₆-alkyl group as defined above wherein at least one of the hydrogenatoms of the alkyl group is replaced by a hydroxyl group.

The terms “C₁₋₆-cyanoalkyl” and “C₁₋₆-alkyl substituted by CN” denote aC₁₋₆-alkyl group as defined above wherein at least one of the hydrogenatoms of the alkyl group is replaced by a CN group.

The terms “halo” and “halogen” refer to fluorine (F), chlorine (Cl),bromine (Br) and iodine (I) with fluorine, chlorine and bromine beingpreferred.

The term “halo-C₁₋₆-alkyl” is synonymous with “C₁₋₆-haloalkyl” or“C₁₋₆-alkyl substituted by halo” and means a C₁₋₆-alkyl group as definedabove wherein at least one of the hydrogen atoms of the alkyl group isreplaced by a halogen atom, preferably fluoro or chloro, most preferablyfluoro. Examples of halo-C₁₋₆-alkyl include but are not limited tomethyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s) aswell as those groups specifically illustrated by the examples hereinbelow. Among the preferred halo-C₁₋₆-alkyl groups are difluoro- ortrifluoro-methyl or -ethyl.

The term “halo-C₁₋₆-alkoxy” is synonymous with “C₁₋₆-haloalkoxy” or“C₁₋₆-alkoxy substituted by halo” and means a C₁₋₆-alkoxy group asdefined above wherein at least one of the hydrogen atoms of the alkylgroup is replaced by a halogen atom, preferably fluoro or chloro, mostpreferably fluoro. Among the preferred halogenated alkoxy groups aredifluoro- or trifluoro-methoxy or -ethoxy.

The term “C₂₋₁₂-alkenyl,” alone or in combination, denotes astraight-chain or branched hydrocarbon residue of 2 to 12 carbon atomscomprising at least one double bond. A preferred sub-group ofC₂₋₁₂-alkenyl is C₂₋₆-alkyenyl. Examples of the preferred alkenyl groupsare ethenyl, propen-1-yl, propen-2-yl(allyl), buten-1-yl, buten-2-yl,buten-3-yl, penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl,hexen-1-yl, hexen-2-yl, hexen-3-yl, hexen-4-yl and hexen-5-yl, as wellas those specifically illustrated by the examples herein below.

The term “5 or 6 membered heteroaryl” means a monovalent aromatic ringof 5 or 6 ring atoms as ring members containing one, two, or three ringheteroatoms selected from N, O, and S, the rest being carbon atoms. 5 or6 membered heteroaryl can optionally be substituted with one, two, threeor four substituents, wherein each substituent may independently beselected from the group consisting of hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-thioalkyl, halo, cyano, nitro, halo-C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl,C₁₋₆-alkoxycarbonyl, amino, C₁₋₆-alkylamino, di(C₁₋₆)alkylamino,aminocarbonyl, and carbonylamino, unless otherwise specificallyindicated. Preferred substituents are halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, hydroxy or cyano. Examples ofheteroaryl moieties include, but are not limited to pyrrolyl, pyrazolyl,imidazolyl, furanyl (synonymous to furyl), thiophenyl (synonymous tothienyl), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, each of which is optionallysubstituted as described herein.

The term “heterocycloalkyl” means a monovalent saturated ring,consisting of one ring of 3 to 7, preferably from 4 to 6 atoms as ringmembers, including one, two, or three heteroatoms selected fromnitrogen, oxygen and sulfur, the rest being carbon atoms. 3 to 7membered heterocycloalkyl can optionally be substituted with one, two,three or four substituents, wherein each substituent is independentlyhydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-thioalkyl, halo, cyano, nitro,halo-C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-alkoxycarbonyl, amino,C₁₋₆-alkylamino, di(C₁₋₆)alkylamino, aminocarbonyl, or carbonylamino,unless otherwise specifically indicated. Preferred substituents arehalo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro,hydroxy or cyano. Examples of heterocyclic moieties include, but are notlimited to, oxiranyl, thiiranyl, oxetanyl, tetrahydro-furanyl,tetrahydro-thiophenyl (synonymous to tetrahydro-thienyl), pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl,isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, ortetrahydropyranyl, each of which is optionally substituted as describedherein.

The term “heterocycle” in the definition “R^(a) and R^(b), R^(c) andR^(d), R^(i) and R^(j), or R^(n) and R^(o), together with the nitrogento which they are bound form a five- or six-membered heterocyclecomprising one or two heteroatoms selected from the group of nitrogen,oxygen and sulfur” means either heterocycloalkyl or heteroaryl in theabove-given sense which may optionally be substituted as describedabove. Preferably, the “heterocycle” may optionally be substituted withone, two or three substituents selected from halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, and cyano. Preferredheterocycles are optionally substituted piperazine, N-methylpiperazine,morpholin, piperidine and pyrrolidine.

The term “C₃₋₆-cycloalkyl” denotes a monovalent or divalent saturatedcarbocyclic moiety consisting of a monocyclic ring. Cycloalkyl canoptionally be substituted with one, two, three or four substituents,wherein each substituent is independently hydroxy, C₁₋₆-alkyl,C₁₋₆-alkoxy, halogen, amino, unless otherwise specifically indicated.Examples of cycloalkyl moieties include optionally substitutedcyclopropyl, optionally substituted cyclobutyl, optionally substitutedcyclopentyl and optionally substituted cyclohexyl as well as thosespecifically illustrated by the examples herein below.

The term “one or more” substituents preferably means one, two or threesubstituents per ring.

“Pharmaceutically acceptable” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The invention further comprises individual optical isomers of thecompounds herein as well as racemic and non-racemic mixtures thereof.

In detail, the present invention provides compounds of formula (I)

wherein

-   -   X is O and Y is CH₂, or    -   X is O and Y is C═O, or    -   X is C═O and Y is NR⁶, or    -   X—Y is CH═CH, or    -   X—Y is CH₂—CH₂, or    -   X is C═O and Y is O, or    -   X is CH₂ and Y is NR⁶, or    -   X is CH₂ and Y is O;        A is selected from the group consisting of

-   R¹, R², R³ and R⁴ are each independently    -   hydrogen,    -   halo,    -   C₁₋₆-alkyl, optionally substituted by OH    -   halo-C₁₋₆-alkyl,    -   C₁₋₆-alkoxy, optionally substituted by OH, or    -   halo-C₁₋₆-alkoxy;-   R⁵ and R^(5′) are each independently hydrogen or methyl;-   R⁶ is hydrogen or C₁₋₆-alkyl;-   R⁷ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH, or    -   —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b);-   R⁸ is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano, or    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;-   R⁹ is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   R¹⁰ is hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy,    halo-C₁₋₆-alkoxy, or —O—C₂₋₁₀-alkenyl;-   R¹¹ is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   or R¹⁰ and R¹¹ are bound together to form a ring with the benzo    moiety, wherein —R¹⁰-R¹¹— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R¹² is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j)    -   —O-benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   —(C₁₋₃-alkylene)-R^(m),        -   wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4-            to 6-membered heterocycloalkyl or 3 to 6-membered            cycloalkyl,            -   each optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano, or    -   —NR^(n)R^(o);-   or R¹¹ and R¹² are bound together to form a ring with the benzo    moiety, wherein —R¹¹-R¹²— is —O—(CH₂)_(n)—C(O)—,    -   —C(O)—(CH₂)_(n)—O—, or    -   —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R^(a), R^(b), R^(i) and R^(j) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-NR^(k)R^(l),        -   wherein R^(k) and R^(l) are each independently hydrogen or            C₁₋₆-alkyl,    -   or R^(a) and R^(b), or R^(i) and R^(j) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;-   R^(c), R^(d), R^(g), R^(h), R^(n) and R^(o) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —C(O)R^(e), or —S(O)₂R^(e)        -   wherein R^(e) is selected from the group of            -   hydrogen,            -   C₁₋₆-alkyl, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano;    -   or R^(c) and R^(d), or R^(n) and R^(o) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;-   R^(f) is selected from    -   hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy; and    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;        or a pharmaceutically acceptable salt thereof.

In certain embodiments of the invention, R^(a) and R^(b), R^(c) andR^(d), R^(i) and R^(j), or R^(n) and R^(o) together with the nitrogen towhich they are bound may form piperazine, 4-(C₁₋₆-alkyl)-piperazine,4-methylpiperazine, morpholine, piperidine or pyrrolidine.

In certain embodiments of the invention, R^(a) and R^(b), R^(c) andR^(d), R^(i) and R^(j), or R^(n) and R^(o) together with the nitrogen towhich they are bound may form 4-methylpiperazine, or morpholine, inparticular morpholine.

In certain embodiments of the invention, wherein R^(m) is a 5- to6-membered heteroaryl, the preferred heteroaryl is selected from thegroup consisting of pyridine, pyrimidine, pyrazine, pyridazine,imidazole, pyrazole, oxazole, and isoxazole. All these residues areoptionally substituted as described herein.

In embodiments of the invention, wherein R^(m) is a 4- to 6-memberedheterocycloalkyl, the preferred heterocycloalkyl is selected from thegroup consisting of pyrrolidine, oxethane, tetrahydropyrane, piperidine,morpholine, and piperazine. All these residues are optionallysubstituted as described herein.

In certain embodiments of the invention,

-   R¹, R², R³ and R⁴ are each independently    -   hydrogen,    -   halo, or    -   C₁₋₆-alkoxy, optionally substituted by OH.

In certain embodiments of the invention, R¹ is hydrogen; R² is hydrogenor C₁₋₆-alkoxy, R³ is hydrogen, halo, or C₁₋₆-alkoxy, optionallysubstituted by OH; and R⁴ is hydrogen.

In certain embodiments all R¹ to R⁴ are hydrogen.

In certain embodiments, one residue of R¹ to R⁴ is halo and the othersare hydrogen.

In certain embodiments, one residue of R¹ to R⁴ is C₁₋₆-alkoxy,optionally substituted by OH, preferably methoxy or —O(CH₂)₂OH, and theothers are hydrogen.

In certain embodiments of the invention, R⁵ and R^(5′) are bothhydrogen, in other embodiments of the invention, R⁵ and R^(5′) are bothmethyl, in other embodiments of the invention, R⁵ is hydrogen and R^(5′)is methyl.

In certain embodiments of the invention, R⁵ is hydrogen, R^(5′) ismethyl, X is O and Y is C═O.

In certain embodiments of the invention, R⁶ is hydrogen or C₁₋₆-alkyl,preferably hydrogen.

In certain embodiments of the invention,

-   R⁷ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH, or    -   —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b),        -   wherein R^(a) and R^(b) are each independently hydrogen or            C₁₋₆-alkyl.

Preferably, R⁷ is hydrogen.

In certain embodiments of the invention,

-   R⁸ is hydrogen,    -   C₁₋₆-alkyl, or    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),        -   wherein R^(c) and R^(d) are each independently            -   hydrogen,            -   —C(O)R^(e), or —S(O)₂R^(e)                -   wherein R^(e) is selected from the group of                -    hydrogen,                -    C₁₋₆-alkyl, and                -    phenyl, optionally substituted by one or more halo,                    halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                    halo-C₁₋₆-alkoxy, nitro, or cyano,    -   —(C₁₋₆-alkylene)-C(O)R^(f),        -   wherein R^(f) is        -   hydrogen,            -   C₁₋₆-alkyl,            -   C₁₋₆-alkoxy, or            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano;    -   benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano, or    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano.

Preferably, R⁸ is hydrogen; C₁₋₆-alkyl, preferably methyl; orC₁₋₆-alkoxy, preferably methoxy or —O-iso-propyl.

In a certain embodiment of the invention, R⁹ is hydrogen, halo orC₁₋₆-alkoxy. Preferably, R⁹ is hydrogen or C₁₋₆-alkoxy.

In certain embodiments of the invention, R⁹ is hydrogen; halo,preferably fluoro, chloro or bromo; C₁₋₆-alkyl, preferably methyl;C₁₋₆-alkoxy, preferably methoxy or —O-iso-propyl; halo-C₁₋₆-alkoxy,preferably trifluoromethoxy; or —O—C₂₋₁₀-alkenyl, preferably allyl.

In certain embodiments of the invention, R¹⁰ is hydrogen; halo,preferably bromo or chloro; C₁₋₆-alkyl, preferably methyl; orC₁₋₆-alkoxy, preferably methoxy.

In certain embodiments of the invention, R¹¹ is hydrogen; halo,preferably bromo or chloro; C₁₋₆-alkyl, preferably methyl; orC₁₋₆-alkoxy, preferably methoxy. More preferably, R¹¹ is hydrogen.

In certain embodiments of the invention

-   R¹² is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h), wherein R^(g) and R^(h) are each        independently        -   hydrogen,        -   C₁₋₆-alkyl,        -   —C(O)R^(e), or —S(O)₂R^(e), wherein R^(e) is selected from            -   hydrogen,            -   C₁₋₆-alkyl, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano;    -   —(C₁₋₁₆-alkylene)-C(O)—NR^(i)R^(j), wherein R^(i) and R^(j) are        each independently        -   hydrogen,        -   C₁₋₆-alkyl,        -   —(C₁₋₆-alkylene)-NR^(k)R^(l),            -   wherein R^(k) and R^(l) are each independently hydrogen                or C₁₋₆-alkyl,        -   or R^(i) and R^(j) together with the nitrogen to which they            are bound form a five or six membered heterocycle comprising            one or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur;    -   —O-benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f), wherein R^(f) is        -   C₁₋₆-alkyl,        -   C₁₋₆-alkoxy, or        -   phenyl, optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano,        -   phenyl, optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano,    -   —(C₁₋₃-alkylene)-R^(m),        -   wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4-            to 6-membered heterocycloalkyl or 3 to 6-membered            cycloalkyl,            -   each optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano, or    -   —NR^(n)R^(o),        -   wherein R^(n) and R^(o) are each independently            -   hydrogen,            -   C₁₋₆-alkyl,        -   or R^(n) and R^(o) together with the nitrogen to which they            are bound form a five or six membered heterocycle comprising            one or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur.

In certain embodiments of the invention,

-   R¹² is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   C₁₋₆-alkoxy, or    -   —NR^(n)R^(o),        -   wherein R^(n) and R^(o) are each independently            -   hydrogen,            -   C₁₋₆-alkyl,        -   or R^(n) and R^(o) together with the nitrogen to which they            are bound form a five or six membered heterocycle comprising            one or two heteroatoms selected from the group of nitrogen,            oxygen.

In certain embodiments of the invention, namely in combination with anyembodiment described herein, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are notsimultaneously hydrogen.

In certain embodiments of the invention, X is O and Y is CH₂, A isselected from the group consisting of (a), (b), (c), (d) and (e); and R¹to R⁵ and R⁷ to R¹² are as defined above.

In certain embodiments of the invention, X is O and Y is C═O, A is (f)or (g), and R¹ to R⁵ and R⁷ to R¹² are as defined above.

In certain embodiments of the invention, X is C═O and Y is NR⁶, A is(f), and R¹ to R¹² are as defined above.

In certain embodiments of the invention, X—Y is CH═CH, and A is (f) or(g), and R¹ to R⁵ and R⁷ to R¹² are as defined above.

In one embodiment

-   -   X is O and Y is CH₂,    -   X is O and Y is C═O,    -   X is C═O and Y is O, or    -   X is CH₂ and Y is O.

In another embodiment

-   -   X is C═O and Y is NR⁶, or    -   X is CH₂ and Y is NR⁶.

In yet another embodiment

-   -   X—Y is CH═CH, or    -   X—Y is CH₂—CH₂.

Preferred X and Y are:

-   -   X is O and Y is CH₂,    -   X is O and Y is C═O,    -   X is C═O and Y is NR⁶,    -   X-Y is CH═CH, or    -   X-Y is CH₂—CH₂.

Preferred compounds of the invention are:

-   1′-(1-Benzothien-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidine],-   1′-[(7-Methoxy-1-benzothien-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine],-   1′-[(3-Isopropoxy-1-benzothien-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine],-   1′-[(5-Methoxy-2,3-dihydro-1-benzothien-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine],-   1′-[(4-Methoxy-7-morpholin-4-yl-1,3-benzothiazol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine],-   1′-[(5-Bromo-7-ethyl-1-benzofuran-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine],-   1′-(1-Benzimidazol-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidine],-   1′-[(5-Methyl-1H-benzimidazol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine],-   1′-[(5-Chloro-1H-benzimidazol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine],-   (1RS,3′SR)-3′-Methyl-1′-[(3-methyl-1H-inden-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-Methoxy-1′-[(3-methyl-1H-inden-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-Methoxy-1′-[(3-methyl-1H-inden-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   1′-(1H-Pyrrolo[2,3-b]pyridin-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-Methoxy-1′-(1H-pyrrolo[2,3-b]pyridin-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   6-(2-Hydroxyethoxy)-1′-(1H-pyrrolo[2,3-b]pyridin-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one,-   5-Bromo-1′-[(3-methyl-1H-inden-2-yl)carbonyl]spiro[indole-3,4′-piperidin]-2(1H)-one,-   1′-[(3-Methyl-1H-inden-2-yl)carbonyl]spiro[indene-1,4′-piperidine],    and-   1′-(1H-Pyrrolo[2,3-b]pyridin-2-ylcarbonyl)spiro[indene-1,4′-piperidine].

The invention also encompasses methods for the treatment ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders which comprisesadministering a therapeutically effective amount of a compound offormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig).

The invention also encompasses a pharmaceutical composition comprising acompound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) anda pharmaceutically acceptable carrier. The pharmaceutical compositionmay further comprise at least one pharmaceutically acceptable excipient.

In a certain embodiment, the compound of the invention of generalformula (I) can be manufactured according to a process comprisingreacting a compound of formula (II):

with a carboxylic acid of the formula III

wherein R¹ to R^(5′), X, Y and A are as defined above.

The synthesis of compounds of general formula (I) will be described inmore detail below and in the examples.

General Scheme A

Compounds of formula (I) can be prepared via an amide coupling between aspiropiperidine derivative of formula (II) and a carboxylic acid A-CO₂H(III), wherein A is defined as hereinabove. The usual reagents andprotocols known in the art can be used to effect the amide coupling.Spiropiperine derivatives of formula (II) and carboxylic acids (III) areeither commercially available or readily prepared using proceduresdescribed hereinafter or using methods known in the art starting fromcommercially available materials. General scheme A is hereinafterfurther illustrated with general procedure I.

General Procedure I: Amide Coupling:

To a 0.1 M stirred solution of a carboxylic acid derivative in CH₂Cl₂are added EDC (1.3 eq), HOBt (1.3 eq), Et₃N (1.3 eq) and thespiropiperidine derivative (1 eq). The mixture is stirred over night atRT and then poured onto water and extracted with CH₂Cl₂. The combinedorganic phases are dried over Na₂SO₄ and concentrated in vacuo. Flashchromatography or preparative HPLC affords the title compound.

The compounds of the present invention exhibit V1a activity, which maybe detected as described below:

V1a Activity Material & Method:

The human V1a receptor was cloned by RT-PCR from total human liver RNA.The coding sequence was subcloned in an expression vector aftersequencing to confirm the identity of the amplified sequence. Todemonstrate the affinity of the compounds from the present invention tothe human V1a receptor binding studies were performed. Cell membraneswere prepared from HEK293 cells transiently transfected with theexpression vector and grown in 20 liter fermenters with the followingprotocol.

50 g of cells were resuspended in 30 ml freshly prepared ice cold Lysisbuffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2 adjusted to pH=7.4+completecocktail of protease inhibitor (Roche Diagnostics)); homogenized withPolytron for 1 min; and sonicated on ice for 2×2 minutes at 80%intensity (Vibracell sonicator). The preparation was centrifuged 20 minat 500 g at 4° C., the pellet was discarded and the supernatantcentrifuged 1 hour at 43,000 g at 4° C. (19,000 rpm). The pellet wasresuspended in 12.5 ml Lysis buffer+12.5 ml Sucrose 20% and homogenizedusing a Polytron for 1-2 min. The protein concentration was determinedby the Bradford method and aliquots were stored at −80° C. until use.For binding studies 60 mg Yttrium silicate SPA beads (Amersham) weremixed with an aliquot of membrane in binding buffer (50 mM Tris, 120 mMNaCl, 5 mM KCl, 2 mM CaCl2, 10 mM MgCl2) for 15 minutes with mixing. 50ul of bead/membrane mixture was then added to each well of a 96 wellplate, followed by 50 ul of 4 nM 3H-Vasopressin (American RadiolabeledChemicals). For total binding measurement 100 ul of binding buffer wereadded to the respective wells, for non-specific binding 100 ul of 8.4 mMcold vasopressin and for compound testing 100 ul of a serial dilution ofeach compound in 2% DMSO. The plate was incubated 1 h at roomtemperature, centrifuged 1 min at 1000 g and counted on a PackardTop-Count. Non-specific binding counts were subtracted from each welland data was normalized to the maximum specific binding set at 100%. Tocalculate an IC 50 the curve was fitted using a non-linear regressionmodel (XLfit), and the Ki was calculated using the Cheng-Prussoffequation.

Example pKi hV1a 1 7.6 2 7.3 4 7.2 6 7.3 9 7.5 10 7.2 14 6.7

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example compounds of formula(Ia), (Ib), (Ic), (Id), (Ie), (If), and (g), and their pharmaceuticallyacceptable acid addition salts, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be in the form of tablets,coated tablets, dragées, hard and soft gelatin capsules, solutions,emulsions or suspensions. The pharmaceutical compositions also can be inthe form of suppositories or injectable solutions.

The pharmaceutical compounds of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic and organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc canbe used as such excipients e.g. for tablets, dragées and hard gelatinecapsules. Suitable excipients for soft gelatine capsules are e.g.vegetable oils, waxes, fats, semi-solid and liquid polyols etc. Suitableexcipients for the manufacture of solutions and syrups are e.g. water,polyols, saccharose, invert sugar, glucose etc. Suitable excipients forinjection solutions are e.g. water, alcohols, polyols, glycerol,vegetable oils etc. Suitable excipients for suppositories are e.g.natural or hardened oils, waxes, fats, semi-liquid or liquid polyolsetc.

Moreover, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The dosage at which the compounds of the invention can be administeredcan vary within wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 10 to 1000 mg per personof a compound of general formula (I) should be appropriate, although theabove upper limit can also be exceeded when necessary.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

EXAMPLE A

Tablets of the following composition can be manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystallinecellulose 34 Magnesium stearate 1 Tablet weight 100

EXAMPLE B

Capsules of the following composition can be manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight 200

The active substance, lactose and corn starch can be firstly mixed in amixer and then in a comminuting machine. The mixture can be returned tothe mixer, the talc can be added thereto and mixed thoroughly. Themixture can be filled by machine into hard gelatine capsules.

EXAMPLE C

Suppositories of the following composition can be manufactured:

mg/supp. Active substance 15 Suppository mass 1285 Total 1300

The suppository mass can be melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C.

Thereupon, the finely powdered active substance can be added thereto andstirred until it has dispersed completely. The mixture then can bepoured into suppository moulds of suitable size, left to cool; thesuppositories can then be removed from the moulds and packedindividually in wax paper or metal foil.

In the following, the synthesis of compounds of formula (I) is furtherexemplified: The compounds of formula I may be prepared in accordancewith the process variants as described above. The starting materialsdescribed in the Example section are either commercially available orare otherwise known or derived from the chemical literature, forinstance as cited below, or may be prepared as described in the Examplessection.

EXAMPLES Example 11′-(1-Benzothien-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: Benzo[b]thiophene-2-carboxylic acid,

ES-MS m/e (%): 350.2 (M+H⁺).

Example 21′-[(7-Methoxy-1-benzothien-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: 7-Methoxy-benzo[b]thiophene-2-carboxylic acid,

ES-MS m/e (%): 380.1 (M+H⁺).

Example 31′-[(3-Isopropoxy-1-benzothien-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: 3-Isopropoxy-benzo[b]thiophene-2-carboxylic acid (described in J.Med. Chem. 1992, 35, 958),

ES-MS m/e (%): 408.2 (M+H⁺).

Example 41′-[(5-Methoxy-2,3-dihydro-1-benzothien-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: 5-Methoxy-2,3-dihydro-benzo[b]thiophene-2-carboxylic acid

ES-MS m/e (%): 381.0 (M+H⁺).

5-Methoxy-2,3-dihydro-benzo[b]thiophene-2-carboxylic acid

From the commercially available 5-methoxy-benzo[b]thiophene-2-carboxylicacid was prepared 5-methoxy-2,3-dihydro-benzo[b]thiophene-2-carboxylicacid by reduction using known procedures. One example is Mg/MeOH.

Example 51′-[(4-Methoxy-7-morpholin-4-yl-1,3-benzothiazol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid(described in patent WO2003045385)

ES-MS m/e (%): 466.6 (M+H⁺).

Example 61′-[(5-Bromo-7-ethyl-1-benzofuran-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: 5-Bromo-7-ethyl-benzofuran-2-carboxylic acid

ES-MS m/e (%): 442.0 (M+H⁺).

Example 71′-(1H-Benzimidazol-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: 1H-Benzoimidazole-2-carboxylic acid,

ES-MS m/e (%): 334.2 (M+H⁺).

Example 81′-[(5-Methyl-1H-benzimidazol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: 5-Methyl-1H-benzoimidazole-2-carboxylic acid,

ES-MS m/e (%): 348.1 (M+H⁺).

Example 91′-[(5-Chloro-1H-benzimidazol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidine] (described in J. Org.Chem. 1976, 41, 2628),

Acid: 5-Chloro-1H-benzoimidazole-2-carboxylic acid,

ES-MS m/e (%): 368.0 (M+H⁺).

Example 10(1RS,3′SR)-3′-Methyl-1′-[(3-methyl-1H-inden-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

Amide coupling according to general procedure I:

Amine: (1RS,3′SR)-3′-Methyl-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(prepared according to WO 9929696)

Acid: 3-Methyl-1H-indene-2-carboxylic acid,

ES-MS m/e (%): 374.5 (M+H⁺).

Example 116-Methoxy-1′-[(3-methyl-1H-inden-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

Amide coupling according to general procedure I:

Amine: 6-Methoxy-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (preparedaccording to EP 722941)

Acid: 3-Methyl-1H-indene-2-carboxylic acid,

ES-MS m/e (%): 390.5 (M+H⁺).

Example 125-Methoxy-1′-[(3-methyl-1H-inden-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

Amide coupling according to general procedure I:

Amine: 5-Methoxy-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (describedin EP 722941)

Acid: 3-Methyl-1H-indene-2-carboxylic acid,

ES-MS m/e (%): 390.5 (M+H⁺).

Example 131′-(1H-Pyrrolo[2,3-b]pyridin-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

Amide coupling according to general procedure I:

Amine: 3H-Spiro[2-benzofuran-1,4′-piperidin]-3-one (preparationdescribed in Organic Process Research & Development (2006), 10(4),822-828.)

Acid: 1H-Pyrrolo[2,3-b]pyridine-2-carboxylic acid,

ES-MS m/e (%): 348.4 (M+H⁺).

Example 146-Methoxy-1′-(1H-pyrrolo[2,3-b]pyridin-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

Amide coupling according to general procedure I:

Amine: 6-Methoxy-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(preparation described in EP 722941)

Acid: 1H-Pyrrolo[2,3-b]pyridine-2-carboxylic acid,

ES-MS m/e (%): 378.4 (M+H⁺).

Example 156-(2-Hydroxyethoxy)-1′-(1H-pyrrolo[2,3-b]pyridin-2-ylcarbonyl)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

Amide coupling according to general procedure I:

Amine: 6-(2-Hydroxyethoxy)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one(preparation described in EP 722941)

Acid: 1H-Pyrrolo[2,3-b]pyridine-2-carboxylic acid,

ES-MS m/e (%): 408.4 (M+H⁺).

6-(2-Hydroxyethoxy)-1′-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

Preparation of N-Methylated Lactone Intermediate:

To a solution of the substituted ortho-bromo benzoic acid (10.9 g, 50mmol) in dry THF (200 ml) at −78° C. n-butyllithium (1.6 M in hexanes)(100 mmol) was added drop wise (3 h) and the resulting solution wasstirred for an additional 2 h at the same temperature. Freshly distilledN-methyl 4-piperidone (7.91 g, 70 mmol) in dry hexane (25 ml) was addedover 30 min at the same temperature. The mixture was then allowed tostir at rt and was finally added to ether (200 ml) and water (300 ml).The basic (aqueous) layer was extracted with ether (5×100 ml) and theaqueous layer was acidified with concentrated hydrochloric acid (pH 2-3)and extracted with ether. The aqueous solution was boiled for 1 h andwas then cooled to 0-5° C. and made alkaline (pH 9-10) with cold aqueoussodium hydroxide. The cold solution was rapidly extracted withchloroform (5×200 ml). The combined chloroform extracts were washed withwater, dried, concentrated to give light yellow solid which was purifiedover neutral alumina eluting with a gradient of 30-50% ethylacetate-hexane to obtain 1.75 g (15%) of N-methylated lactone as whitesolid. 1H-NMR (CDCl3, 400 MHz): δ1.68-1.75 (m, 2H), 2.18-2.19 (m, 1H),2.38 (s, 3H), 2.44-2.52 (m, 2H), 2.68-2.84 (m, 2H), 2.84-2.85 (m, 1H),7.02-7.05 (m, 1H), 7.19-7.22 (m, 1H), 7.84-7.87 (m, 1H); FIA-MS: 236(M+1).

Preparation of Cyano-Piperidine Intermediate:

To a solution of the N-methylated lactone from above (1.17 g, 5 mmol) indry chloroform (10 ml) was added cyanogenbromide (60 mnol) and theresulting solution was refluxed for 36 h. The reaction mixture wasextracted with 5% HCl (5 ml) and then with water (2.5 ml). Thechloroform solution was dried (anhydrous MgSO4) and concentrated to givea pale yellow solid which was chromatographed over SiO2 eluting with 1%MeOH—CH2Cl2 to give 858 mg (70%) of the desired Cyano-piperidine aswhite solid. 1H-NMR (CDCl3, 400 MHz): δ1.72-1.76 (m, 2H), 2.22-2.30 (m,1H), 3.48-3.60 (m, 4H), 7.09-7.11 (m, 1H), 7.11-7.28 (m, 1H), 7.89-7.92(m, 1H); IR (KBr): 3492, 3043, 2216, 1760, 1602, 1478 cm1.

Preparation of6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one

The above cyano-piperidine (1.23 g, 5 mmol) was heated with ethyleneglycol (5 ml) and sodium hydroxide (0.82 g, 20.5 mmol) for 15-20 min at130° C. Most of the ethylene glycol was removed by distillation underhigh vacuum. The residual reaction mixture was diluted with water andextracted repeatedly with chloroform. The combined organics was driedand concentrated to give a semi solid material which was purified overAl2O3 column upon elution with 5-7% MeOH2CI2 containing NH3 (aqueous) toyield 789 mg (60%) of6-(2-hydroxyethoxy)-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one as paleyellow solid. 1H-NMR (d6-DMSO, 400 MHz): δ1.47-1.50 (m, 2H), 2.03-2.10(m, 2H0, 2.79-2.85 (m, 2H), 2.95-2.97 (m, 2H), 3.73-3.76 (m, 2H),4.12-4.14 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 7.20 (s, 1H), 7.69 (d, J=8.4Hz, 1H); 13C-NMR (d6-DMSO, 100 MHz): □□35.9, 42.3, 59.3, 70.4, 84.6,106.4, 116.6, 117.0, 126.8, 156.9, 163.9, 168.5; FIA-MS: 264.3 (M+1).

Example 165-Bromo-1′-[(3-methyl-1H-inden-2-yl)carbonyl]spiro[indole-3,4′-piperidin]-2(1H)-one

Amide coupling according to general procedure I:

Amine: 5-Bromo-spiro[indole-3,4′-piperidin]-2(1H)-one (prepareddescribed herein below)

Acid: 3-Methyl-1H-indene-2-carboxylic acid,

ES-MS m/e (%): 437.4 (M+H⁺).

5-bromo-spiro[indole-3,4′-piperidin]-2(1H)-one

1,5-Dichloro-3-methyl-3-azapentane hydrochloride 3

Formic acid (10.0 g; 0.2 mol) and 37% formaldehyde (20 ml) were mixed ina 250 ml round-bottom flask equipped with reflux condenser.1,5-Dichloro-3-azapentane, hydrochloride (17.0 g; 0.1 mol) was added andthe solution was heated with magnetic stirring at 100 C. After 3 h thetemperature was increased to 120 C for 20 min and finally allowed tocool to room temperature before the solvent was evaporated in vacuo toafford 3 as white solid in quantitative yield. 1HNMR (CD3OD, 400 MHz) δ3.0 (s, 3H); 3.45 (br s, 2H); 3.62 (br s, 2H); 4.07 (br s, 4H).

1,2-Benzo-8-methyl-3,8-diazaspiro[4,5]decane-4-one 5

A solution of oxindole 4 (6.25 g, 47 mmol) in THF (500 ml) was cooled to−78 C and to it a solution of sodium hexamethyldisilazide (43 g, 235mmol) in THF (300 ml) was added drop wise under N2 atmosphere. Afterstirring at −78 C for 45 min, N-methylbis (2-chloromethyl) aminehydrochloride (9 g, 47 mmol) was added, as a solid. The reaction mixturewas stirred at −78 C for 1 h and at room temperature for 24 h. Afterquenching with H2O (90 ml), the mixture was extracted with ethyl acetate(3×100 ml). The organic extracts were washed with brine (25 ml), driedand the solvent removed in vacuo. Silica gel chromatography (5-50%MeOH/CH₂Cl₂, gradient) gave 6 g (57%) of 5 as a solid. 1HNMR (CD3OD, 400MHz) δ 1.84 (m, 2H); 2.51 (m, 2H); 2.62 (s, 3H); 3.02 (m, 2H); 3.37 (m,2H); 6.82 (d, 1H, J=7.68 Hz); 6.94 (t, 1H, J=7.58 Hz); 7.12 (t, 1H,J=7.7 Hz); 7.26 (d, 1H, J=9 Hz); 9.27 (br s, 1H).

5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4′-piperidine]-1′methyl 6

A solution of 1,2-Benzo-8-methyl-3,8-diazaspiro[4,5]decane-4-one (6.3 g,29.1 mmol) in CH₃CN (100 ml) and MeOH (5 ml) was cooled to −5° C. andNBS (7.8 g, 44 mmol) was slowly added with stirring. The reactionmixture was stirred for 3.5 h at 0° C. Solvent was removed by vacuo. Theresidue was purified by silica gel chromatography (2-20% MeOH/CH₂Cl₂) togive 6 g as a solid. The solid compound was dissolved in ethyl acetate(600 ml) and washed with saturated aqueous NaHCO₃ solution, dried(Na₂SO₄). Evaporation of the solvent in vacuo gave 4.2 g (47%) of 6.¹HNMR (CD₃OD, 400 MHz) δ 7.51 (d, J=1.8 Hz, 1H), 7.35 (dd, J=1.9 and 8.2Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 2.93 (m, 2H), 2.67 (m, 2H), 2.41 (s,3H), 1.86 (m, 4H).

5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4′-piperidine]-1′-cyano 7

5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4′-piperidine]-1′-methyl 6(4.6 g, 15.6 mmol) was dissolved in chloroform (700 ml) and treated withCNBr (22 g, 209.5 mmol) at room temperature. The mixture was heated toreflux for 24 h. The reaction mixture was cooled, diluted with methylenechloride (300 ml) and washed with 10% aqueous K₂CO₃ solution (2×100 ml).After the mixture was dried (Na₂SO₄) and concentrated, the residue waspurified by silica gel chromatography (0-5% MeOH/CH₂Cl₂) to gave 7 as asolid 3.9 g (82%). ¹HNMR (CDCl₃, 400 MHz) δ 7.52 (d, J=1.8 Hz, 1H), 7.37(dd, J=1.8 and 8.2 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 3.83 (m, 2H), 3.41(m, 2H), 2.00 (m, 2H), 1.86 (m, 2H).

5-Bromo-spiro[indole-3,4′-piperidin]-2(1H)-one 2

5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4′-piperidine]-1′-cyano 7(3.3 g, 10.8 mmol) was suspended in ethylene glycol (10 ml). The mixturewas treated in NaOH (1.8 g, 45 mmol) and heated to 130° C. for 15 min.It was diluted with methylene chloride (500 ml) and washed with 10%aqueous K₂CO₃ (2×100 m). The organic layer was dried (Na₂SO₄) andconcentrated and residue purified by silica gel chromatography (30%MeOH/CH₂Cl₂) to gave 2 as a light ceramic white solid 1.8 g (60%), mp256-258° C. ¹HNMR (DMSO-d₆, 400 MHz) δ 10.6 (br s, 1H, NH), 7.57 (d,J=1.84 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.05 (brs, 1H, NH), 3.06 (m, 2H), 2.84 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H), ¹³CNMR (DMSO-d₆, 100 MHz) δ 180.93, 140.64, 137.98, 130.42, 126.75, 113.20,111.45, 46.24, 40.92, 32.94. Anal. Calcd for C₁₂H₁₃BrN₂O: C, 51.26; H,4.66; N, 9.9. Found: C, 50.87; H, 4.91; N, 9.67.

Example 171′-[(3-Methyl-1H-inden-2-yl)carbonyl]spiro[indene-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: Spiro[indene-1,4′-piperidine],

Acid: 3-Methyl-1H-indene-2-carboxylic acid,

ES-MS m/e (%): 342.5 (M+H⁺).

Example 181′-(1H-Pyrrolo[2,3-b]pyridin-2-ylcarbonyl)spiro[indene-1,4′-piperidine]

Amide coupling according to general procedure I:

Amine: Spiro[indene-1,4′-piperidine],

Acid: 1H-Pyrrolo[2,3-b]pyridine-2-carboxylic acid,

ES-MS m/e (%): 330.4 (M+H⁺).

1. A compound of the general formula (I)

wherein X is C═O and Y is NR⁶, or X is CH₂ and Y is NR⁶; A is selectedfrom the group consisting of

R¹, R², R³ and R⁴ are each independently hydrogen, halo, C₁₋₆-alkyl,optionally substituted by OH halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, optionallysubstituted by OH, or halo-C₁₋₆alkoxy; R⁵ and R^(5′) are eachindependently hydrogen or methyl; R⁶ is hydrogen or C₁₋₆-alkyl; R⁷ ishydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH, or—(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b); R⁸ is hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), —(C₁₋₆-alkylene)-C(O)R^(f),benzyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; R⁹ is hydrogen, halo,C₁₋₆-alkyl, or C₁₋₆-alkoxy; R¹⁰ is hydrogen, halo, C₁₋₆-alkyl,halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, or —O—C₂₋₁₀-alkenyl; R¹¹is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy; or R¹⁰ and R¹¹ are boundtogether to form a ring with the benzo moiety, wherein —R¹⁰-R¹¹— is—O—(CH₂)_(n)—O— wherein n is 1 or 2; R¹² is hydrogen, C₁₋₆-alkyl,optionally substituted by CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h),—(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j) —O-benzyl, optionally substituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo, cyano, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, —(C₁₋₆-alkylene)-C(O)R^(f), phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, —(C₁₋₃-alkylene)-R^(m),wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4- to 6-memberedheterocycloalkyl or 3 to 6-membered cycloalkyl, each optionallysubstituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or —NR^(n)R^(o); or R¹¹and R¹² are bound together to form a ring with the benzo moiety, wherein—R¹¹-R¹²— is —O—(CH₂)_(n)—C(O)—, —C(O)—(CH₂)_(n)—O—, or —O—(CH₂)_(n)—O—wherein n is 1 or 2; R^(a), R^(b), R^(i) and R^(j) are eachindependently hydrogen, C₁₋₆-alkyl, —(C₁₋₆-alkylene)-NR^(k)R^(l),wherein R^(k) and R^(l) are each independently hydrogen or C₁₋₆-alkyl,or R^(a) and R^(b), or R^(i) and R^(j) together with the nitrogen towhich they are bound form a five or six membered heterocycle comprisingone or two heteroatoms selected from the group of nitrogen, oxygen andsulfur; R^(c), R^(d), R^(g), R^(h), R^(n) and R^(o) are eachindependently hydrogen, C₁₋₆-alkyl, —C(O)R^(e), or —S(O)₂R^(e) whereinR^(e) is selected from the group of hydrogen, C₁₋₆-alkyl, and phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or R^(c) and R^(d), orR^(n) and R^(o) together with the nitrogen to which they are bound forma five or six membered heterocycle comprising one or two heteroatomsselected from the group of nitrogen, oxygen and sulfur; R^(f) isselected from the group of hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy; andphenyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein R^(a) and R^(b), R^(c) and R^(d), R^(i) and R^(j), or R^(n) andR^(o) together with the nitrogen to which they are bound formpiperazine, 4-(C₁₋₆-alkyl)-piperazine, 4-methylpiperazine, morpholine,piperidine or pyrrolidine.
 3. The compound of claim 1, wherein R^(m) isa 5- to 6-membered heteroaryl selected from the group consisting ofpyridine, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole,oxazole, and isoxazole.
 4. The compound of claim 1, wherein R^(m) is a4- to 6-membered heterocycloalkyl selected from the group consisting ofpyrrolidine, oxethane, tetraahydropyrane, piperidine, morpholine, andpiperazine.
 5. The compound of claim 1, wherein R¹, R², R³ and R⁴ areeach independently hydrogen, halo, or C₁₋₆-alkoxy, optionallysubstituted by OH.
 6. The compound of claim 1, wherein R¹ is hydrogen;R² is hydrogen or C₁₋₆-alkoxy; R³ is hydrogen, halo, or C₁₋₆-alkoxy,optionally substituted by OH; and R⁴ is hydrogen.
 7. The compound ofclaim 1, wherein R¹, R², R³, and R⁴ all are hydrogen.
 8. The compound ofclaim 1, wherein one of R¹, R², R³, and R⁴ is halo and the others arehydrogen.
 9. The compound of claim 1, wherein one of R¹, R², R³, and R⁴is C₁₋₆-alkoxy, optionally substituted by OH.
 10. The compound of claim1, wherein R⁵ and R^(5′) are both hydrogen; are both methyl; or one ishydrogen and the other methyl.
 11. The compound of claim 1, wherein R⁶is hydrogen or C₁₋₆-alkyl.
 12. The compound of claim 1, wherein R⁷ ishydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH, or—(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b), wherein R^(a) and R^(b) are eachindependently hydrogen or C₁₋₆-alkyl.
 13. The compound of claim 1,wherein R⁸ is hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy,—(C₁₋₆-alkylene)-NR^(c)R^(d), wherein R^(c) and R^(d) are eachindependently hydrogen, or —C(O)R^(e), or —S(O)₂R^(e) wherein R^(e) isselected from the group of hydrogen, C₁₋₆-alkyl, and phenyl, optionallysubstituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano,—(C₁₋₆-alkylene)-C(O)R^(f), wherein R^(f) is selected from the group ofhydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, and phenyl, optionally substituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano; benzyl, optionally substituted by oneor more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl, optionally substituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano.
 14. The compound of claim 1, whereinR⁸ is hydrogen, C₁₋₆-alkyl, or C₁₋₆-alkoxy.
 15. The compound of claim 1,wherein R⁹ is hydrogen, or C₁₋₆-alkoxy.
 16. The compound of claim 1,wherein R¹⁰ is hydrogen, halo, C₁₋₆-alkyl or C₁₋₆-alkoxy.
 17. Thecompound of claim 1, wherein R¹¹ is hydrogen, halo, C₁₋₆-alkyl, orC₁₋₆-alkoxy.
 18. The compound of claim 1, wherein R¹¹ is hydrogen. 19.The compound of claim 1, wherein R¹² is hydrogen, C₁₋₆-alkyl, optionallysubstituted by CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h), wherein R^(g) andR^(h) are each independently hydrogen, C₁₋₆-alkyl, or —C(O)R^(e), or—S(O)₂R^(e), wherein R^(e) is selected from hydrogen, C₁₋₆-alkyl, andphenyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano;—(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j), wherein R^(i) and R^(j) are eachindependently hydrogen, C₁₋₆-alkyl, or —(C₁₋₆-alkylene)-NR^(k)R^(l),wherein R^(k) and R^(l) are each independently hydrogen or C₁₋₆-alkyl,or R^(i) and R^(j) together with the nitrogen to which they are boundform a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur;—O-benzyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo,cyano, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl,—(C₁₋₆-alkylene)-C(O)R^(f), wherein R^(f) is C₁₋₆-alkyl, C₁₋₆-alkoxy, orphenyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, —(C₁₋₃-alkylene)-R^(m),wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4- to 6-memberedheterocycloalkyl or 3 to 6-membered cycloalkyl, each optionallysubstituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or —NR^(n)R^(o), whereinR^(n) and R^(o) are each independently hydrogen, C₁₋₆-alkyl, or R^(n)and R^(o) together with the nitrogen to which they are bound form a fiveor six membered heterocycle comprising one or two heteroatoms selectedfrom the group of nitrogen, oxygen and sulfur.
 20. The compound of claim1, wherein R¹² is hydrogen, C₁₋₆-alkyl, optionally substituted by CN orOH, C₁₋₆-alkoxy, or —NR^(n)R^(o), wherein R^(n) and R^(o) are eachindependently hydrogen, C₁₋₆-alkyl, or R^(n) and R^(o) together with thenitrogen to which they are bound form a five or six membered heterocyclecomprising one or two heteroatoms selected from the group of nitrogen,oxygen.
 21. The compound of claim 1, wherein X is C═O and Y is NR⁶, andA is (f).
 22. The compound of claim 1, which is5-Bromo-1′-[(3-methyl-1H-inden-2-yl)carbonyl]spiro[indole-3,4′-piperidin]-2(1H)-one.23. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I)

wherein X is C═O and Y is NR⁶, or X is CH₂ and Y is NR⁶; A is selectedfrom the group consisting of

R¹, R², R³ and R⁴ are each independently hydrogen, halo, C₁₋₆-alkyl,optionally substituted by OH halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, optionallysubstituted by OH, or halo-C₁₋₆alkoxy; R⁵ and R^(5′) are eachindependently hydrogen or methyl; R⁶ is hydrogen or C₁₋₆-alkyl; R⁷ ishydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH, or—(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b); R⁸ is hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), (C₁₋₆-alkylene)-C(O)R^(f),benzyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; R⁹ is hydrogen, halo,C₁₋₆-alkyl, or C₁₋₆-alkoxy; R¹⁰ is hydrogen, halo, C₁₋₆-alkyl,halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, or —O—C₂₋₁₀-alkenyl; R¹¹is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy; or R¹⁰ and R¹¹ are boundtogether to form a ring with the benzo moiety, wherein —R¹⁰-R¹¹— is—O—(CH₂)_(n)—O— wherein n is 1 or 2; R¹² is hydrogen, C₁₋₆-alkyl,optionally substituted by CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h),—(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j) —O-benzyl, optionally substituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo, cyano, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, —(C₁₋₆-alkylene)-C(O)R^(f), phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, —(C₁₋₃-alkylene)-R^(m),wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4- to 6-memberedheterocycloalkyl or 3 to 6-membered cycloalkyl, each optionallysubstituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or —NR^(n)R^(o); or R¹¹and R¹² are bound together to form a ring with the benzo moiety, wherein—R¹¹-R¹²— is —O—(CH₂)_(n)—C(O)—, —C(O)—(CH₂)_(n)—O—, or —O—(CH₂)_(n)—O—wherein n is 1 or 2; R^(a), R^(b), R^(i) and R^(j) are eachindependently hydrogen, C₁₋₆-alkyl, or —(C₁₋₆-alkylene)-NR^(k)R^(l),wherein R^(k) and R^(l) are each independently hydrogen or C₁₋₆-alkyl,or R^(a) and R^(b), or R^(i) and R^(j) together with the nitrogen towhich they are bound form a five or six membered heterocycle comprisingone or two heteroatoms selected from the group of nitrogen, oxygen andsulfur; R^(c), R^(d), R^(g), R^(h), R^(n) and R^(o) are eachindependently hydrogen, C₁₋₆-alkyl, or —C(O)R^(e), or —S(O)₂R^(e)wherein R^(e) is selected from the group of hydrogen, C₁₋₆-alkyl, andphenyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or R^(c) andR^(d), or R^(n) and R^(o) together with the nitrogen to which they arebound form a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur;R^(f) is selected from the group of hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy;and phenyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.